The invention relates to novel derivatives of polyamine-linked acridines and salts thereof and the processes and intermediates for their preparation.
DNA intercalating drugs are a class of antitumor agents that interact with the DNA double helix. DNA intercalating drugs include synthetic intercalating drugs, anthracyclines and other intercalating antitumor antibiotics.
Several antitumor agents are traditionally clinically useful, such as actinomycin D, adriamycin and daunomycin. Recently, several intercalating antitumor agents were also developed or under clinical trials. Amsacrine, an aminoacridine, and mitoxantrone hydrochloride, an anthracenedione, are synthetic intercalating drugs that were launched in 1982 and 1984, respectively. Bisanthrene hydrochloride, an anthracene bishydrazone cytostatic intercalant, was launched in 1989 for the treatment of nonlymphocytic leukemia. Three examples of anthrapyrazoles under clinical trial include: piroxantrone; iosoxantrone hydrochloride; and teloxantrone. Other synthetic DNA intercalating antitumor drugs include crisnatol mesylate, polyamine-linked naphthalimide antitumor agents, quinobenzoxazine antineoplastic compounds, and aza-anthracenedione antitumor agents.
DNA polyintercalating drugs based on polyamine-linked acridine dimers have been shown to be fluorescent probes of DNA sequence. See, Le Pecq, J. B., Le Bret, M., Barbet, J., Roques, B. Proc.Nat.Acad.Sci, USA Vol.72. No.8. 2915 (1975). The effect of the rigidity of the polyamine linking chain on the DNA-intercalating properties were also studied. See, Markovits, J., Garbay-Jaureguiberry, C., Roques, B., Le Pecq, J. B. Eur. J. Biochem. 180, 359 (1989). One can consider these drugs to consist of a DNA intercalation domain (i.e., the acridine ring region) and a protein binding domain (i.e., sidearms or linkers).